11-124885112-G-A

Position:

• chr11-124885112-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019055.6(ROBO4):​c.2930C>T​(p.Pro977Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROBO4 NM_019055.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

Genes affected

ROBO4 (HGNC:17985): (roundabout guidance receptor 4) Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. [provided by Alliance of Genome Resources, Apr 2022]

ROBO4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16705137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO4	NM_019055.6	c.2930C>T	p.Pro977Leu	missense_variant	17/18	ENST00000306534.8	NP_061928.4
ROBO4	NM_001301088.2	c.2495C>T	p.Pro832Leu	missense_variant	17/18		NP_001288017.1
ROBO4	XM_006718861.3	c.2816C>T	p.Pro939Leu	missense_variant	17/18		XP_006718924.1
ROBO4	XM_011542875.2	c.1604C>T	p.Pro535Leu	missense_variant	10/11		XP_011541177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8	c.2930C>T	p.Pro977Leu	missense_variant	17/18	1	NM_019055.6	ENSP00000304945.3
ROBO4	ENST00000534407.5	n.3137C>T		non_coding_transcript_exon_variant	4/5	1
ROBO4	ENST00000533054.5	c.2495C>T	p.Pro832Leu	missense_variant	17/18	2		ENSP00000437129.1
ENSG00000254568	ENST00000524453.1	n.673+749G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.2930C>T (p.P977L) alteration is located in exon 17 (coding exon 17) of the ROBO4 gene. This alteration results from a C to T substitution at nucleotide position 2930, causing the proline (P) at amino acid position 977 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.081
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.011	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.053	B;.
Vest4		0.25
MutPred		0.32		Loss of glycosylation at P977 (P = 0.0207);.;
MVP		0.83
MPC		0.079
ClinPred		0.53	D
GERP RS		3.8
Varity_R		0.084
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1946689605; hg19: chr11-124755008;